Abstract: One of the characteristics of Alzheimer's disease is the presence of neurotoxic deposits in brain tissues, which are largely made up of fibrils comprised of misfolded Amyloid-? (A?) protein. The elucidation of the factors responsible for formation and stabilization of the fibrils and other aggregates is one of the key aspects in discovering the molecular basis of the disease. Our approach will complement and extend the work of other groups that study static structures and bulk properties of the fibrils. Intrinsic flexibility is one of the most important understudied contributions toward stabilization of fibrils and nonfibrillar aggregates. With the abundance of naturally occurring mutations and post-translational modifications of A?, the long- term goal of our research is to identify common dynamical features important in defining aggregation and nucleation propensities. In this proposal, we will conduct site-specific investigations to determine differences in the dynamics between polymorphic states of the fibrils comprised of native A?, as well as in naturally-occurring mutants and post-translational modifications that are known to affect the nucleation process, promote aggregation of the fibrils, and respond in altered fashion to modulation of aggregation by metal ions such as zinc. Special focus will be placed on the unstructured N-terminal domain containing a number of such modifications and regulatory sites. We will utilize deuterium solid-state nuclear magnetic resonance spectroscopy, which is exquisitely sensitive to dynamics, as well as computational modeling necessary for elucidation of dynamical modes and parameters based on the spectroscopic data. The obtained site-specific mechanistic information will shed light on the dynamical modes that are important for driving aggregation and ultimately will contribute to the rational design of pharmaceutical agents that could shunt A? toward less toxic forms of fibrils. This project will greatly enhance research opportunities for undergraduate and master- level students at CU Denver, who are seeking to broaden their education and build-up professional experiences to enter a variety of biomedical fields. The PI has the necessary expertise, passion, and experience to provide outstanding training for these students.